This proposal studies microhemorrhages that are associated with Alzheimer's disease (AD). Alzheimer's disease (AD) is a chronic, neurodegenerative disease characterized by extracellular amyloid plaques, intracellular neurofibrillary tangles and neuron loss. There is also a vascular component consisting of amyloid deposition in the vasculature termed cerebral amyloid angiopathy (CAA). Microhemorrhages are frequently observed in association with CAA. We observe an inflammatory response to these microhemorrhages consisting of activation of microglia and astrocytes. While the amyloid plaques and neurofibrillary tangles have been, and continues to be, extensively studied, the vascular component of AD remains relatively understudied. The aim of this research proposal is to determine the sequence of events leading to microhemorrhage. We will approach this by using two transgenic mouse models, the APPSwDI/ApoE4 and the APPswe/NOS2-/-. These models are particularly useful since the APPSwDI/ApoE4 mouse develops CAA but does not develop any microhemorrhages while the APPswe/NOS2-/- mouse develops only moderate CAA, but multiple microhemorrhages. We will use immunohistochemical and molecular methods to establish a time-course of pathology and gene expression. We will then manipulate these mice using anti-inflammatory compounds to reduce inflammation and also lipopolysaccharide to induce more inflammation. We will perform these studies in young mice, prior to amyloid deposition, and old mice, with significant amyloid deposition, and will assess any changes in pathology or gene expression. This will assist us in determining the relationship between vascular amyloid and inflammation in the development of microhemorrhages and breakdown of the neurovascular unit in Alzheimer's disease. Spatial memory testing using the radial-arm water maze will also be performed in the anti-inflammatory study to determine the functional consequence of these vascular changes. Overall, the studies to be performed in this research proposal will advance the understanding of the causes of microhemorrhage and the role of the neurovascular unit in Alzheimer's disease.